Conventionally, various methods for administrating drug have been known such as oral, rectal, intracutaneous or intravenous administration, and among them oral administration is employed most widely. However, oral administration has some defaults, for example, that a drug is prone to a first pass effect in the liver, and that the blood level of a drug becomes transiently higher than that required after it is administered orally. In addition, such adverse reactions as gastrointestinal disturbance, nausea, anorexia and so on have been often reported after oral administration. Furthermore, considering an increase in the number of patients with difficulty in deglutition in this aged society, pharmaceutical formulations easier to take are required clinically. Therefore, patch formulations for external use have been actively developed and such products are also marketed, because they can eliminate these defaults of oral administration and can be taken more safely and more continually by patients as pharmaceutical formulation easy to take.
But, many drugs have so low percutaneous absorption that their patch formulations for external use are difficult to develop, thus hindering such formulations from functioning adequately. In other words, normal skin has inherently a barrier function to prevent foreign bodies from intruding into the body, whereby many drugs are not well absorbed percutaneously when a typical base is used for such patch formulations.
It has thus been attempted to elevate percutaneous absorption of drugs through the corneal layer of epidermis, generally by means of addition of a so-called percutaneous absorption enhancer into the base. For example, absorption promoting compositions comprising a lower alkyl amide, such as a combination of dimethyl acetamide with ethyl alcohol, isopropyl alcohol or isopropyl palmitate (U.S. Pat. No. 3,472,931); a combination of 2-pyrrolidone with a suitable oil, or a straight-chain fatty acid with an alcoholic ester (U.S. Pat. No. 4,017,641); a lower alcohol and an alcohol having carbon atoms of 7 to 20; an aliphatic acid hydrocarbon having carbon atoms of 5 to 30, an alcoholic ester of an aliphatic carboxylic acid having carbon atoms of 19 to 26, a mono- or di-ether having carbon atoms of 10 to 24 or a combination of a ketone having carbon atoms of 11 to 15 (Japanese Patent Laid-Open No. 61-249934) and the like were disclosed. However, these conventional absorption enhancers and absorption promoting compositions are not sufficiently safe to the skin. In addition, in a patch formulation for external use containing a basic drug in the form of an acid addition salt, the drug could hardly be expected to exhibit its effect.
Further, a technique of using a combination of a drug and an organic acid is also described for patch formulations for external use. For example, a tape formulation where betamethasone valerate and an organic acid are combined together with a natural rubber based adhesive (Japanese Patent Laid-Open No. 56-61312), a tape formulation where a non-steroidal anti-inflammatory analgesic and an organic acid are combined together with an acrylic adhesive (Japanese Patent Laid-Open No. 62-126119), also a poultice-type formulation where methyl salicylate as a drug component, an emulsifier, an organic acid, a plasticizer, a tackifying resin and water are combined together with styrene-isoprene-styrene block copolymer (Japanese Patent Laid-Open No. 63-159315) and the like were disclosed. In any of these specifications, however, no organic acid salt is used, and the organic acid is used to improve stability, elevate solubility and adjust pH, but not to elevate percutaneous absorption of the drug. Furthermore, any drug in these specifications is acidic or neutral, and use of the organic acid therein is not intended to elevate either skin permeation or stability of a basic drug through ion pair formation as in the present invention.
Also, another technique is attempted to elevate skin permeation of a basic physiologically active substance. For example, a tape formulation where citric acid and isoproterenol hydrochloride are combined together with an acrylic adhesive (Japanese Patent Laid-Open No. 63-79820), and a tape formulation where an organic acid and vinpocetine are combined together with an acrylic adhesive (Japanese Patent Laid-Open No. 5-25039) were described. However, these formulations have a problem of irritability when detached, and they cannot release a sufficient amount of a drug for therapy.
Also, yet another technique of combining a drug and an organic acid as a percutaneous dosage formulation is disclosed. For example, a formulation containing an organic acid and a glycol together with a salt of a non-steroidal anti-inflammatory analgesic (Japanese Patent Laid-Open No. 62-181226), and a patch formulation comprising an alkaline metal salt of a non-steroidal anti-inflammatory analgesic and an organic acid more acidic than the free form of the non-steroidal anti-inflammatory analgesic (Japanese Patent Publication No. 7-47535) were described. These disclosures, however, do not relate to basic drugs but to acidic drugs. Also disclosed is a formulation where a basic drug or its salt, an alcohol having carbon atoms of 2 to 5, an organic acid having carbon atoms of 2 to 5 and a carboxylic acid ester having carbon atoms of 16 to 20 are combined, although application of an organic acid salt is not described therein.
Yet another technique to formulate a patch formulation is disclosed in WO 96/16642, where an organic acid salt is contained together with the salt form of a basic drug, but it is not disclosed that a combination of an organic acid with an organic acid salt may elevate the skin permeability of the drug, nor the physical stability of the patch formulation for external use, such as adhesiveness or appearance.
Accordingly, no patch formulation for external use has yet been known that contains a basic drug in the form of an acid addition salt, thereby possessing excellent stability and also a desirable percutaneous absorption property of the drug therein.